Understanding RP2 (Recommended Phase 2 Dose)
RP2 refers to the Recommended Phase 2 Dose, which is the dose determined in phase I clinical trials to be used in subsequent phase II trials of cancer therapeutics. 1
Definition and Traditional Approach
RP2 (Recommended Phase 2 Dose) has traditionally been established through the following process:
- In oncology drug development, the RP2D has historically been determined based on toxicity parameters
- For decades, the dosage of cancer therapeutics has been guided by paradigms used for early cytotoxic drugs
- The traditional approach assumed:
- A dose-response relationship exists for efficacy
- The therapeutic window is relatively small
- Toxicity is directly related to drug exposure and efficacy
- It's appropriate to err on the side of higher doses given rapidly progressing disease 1
Evolution of RP2D Determination
The traditional approach to RP2D has significant limitations in modern oncology:
- For cytotoxic agents, the assumption that the optimal dose was the Maximum Tolerated Dose (MTD) was sometimes confirmed retrospectively
- However, very few new cancer therapeutics in development are cytotoxic agents
- For targeted agents (e.g., selective kinase inhibitors) or monoclonal antibodies, the optimal dose is not necessarily the MTD 1
Problems with Traditional RP2D Approach
The MDICT Taskforce (supported by ESMO) identified several issues with the traditional RP2D determination:
- MTD-based dosing often results in unnecessary morbidity
- In some cases, toxicity can even be fatal
- For protein-based therapeutics such as monoclonal antibodies, phase I studies may never reach the MTD
- Many drugs are routinely used at doses lower than those in the product monograph/prescribing information due to tolerability issues
- Early clinical trials are often limited to highly selected patient populations
- Protocols may consider toxicity only from the first one or two cycles, even though some drugs elicit >50% of severe toxicities after the dose-limiting toxicity period
- Dosage recommendations do not usually consider patient perceptions of chronic mild to moderate symptomatic adverse events 1
Current Challenges in RP2D Determination
The current approach to RP2D faces several challenges:
- Modern drug development typically involves a single large multi-centric phase I trial with multiple endpoints that may not focus on dose optimization
- Only one schedule may be tested in phase I and then used for subsequent trials
- Dose optimization is often deferred to later trial phases or after marketing, if conducted at all
- Given interpatient variation in drug absorption and metabolism (particularly for oral agents), a single RP2D inevitably means some patients will be underdosed while many will be overdosed 1
Recommended Improvements
The MDICT Taskforce suggests the following improvements to RP2D determination:
- Revise standard oncology phase I designs to improve dosage selection
- Consider benefits such as reduced morbidity and mortality for patients
- Reduce costs due to adverse effects
- Potentially faster new drug approvals if the need to repeat studies to refine dosage late in development is minimized
- For marketed drugs, conduct post-marketing dose optimization studies to reduce costs to patients and payers 1
Recent Regulatory Initiatives
In 2021, the FDA Oncology Center of Excellence announced an emphasis on dose optimization for oncology drugs (Project Optimus), indicating a regulatory shift toward more thoughtful dose determination beyond simply identifying the MTD 1.
This evolution in RP2D determination represents an important shift in oncology drug development toward more patient-centered approaches that balance efficacy with quality of life considerations.